Polydatin mediates Parkin-dependent mitophagy and protects against mitochondria-dependent apoptosis in acute respiratory distress syndrome
Polydatin mediates Parkin-dependent mitophagy and protects against mitochondria-dependent apoptosis in acute respiratory distress syndrome
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虎杖苷介导 Parkin 依赖性线粒体自噬并防止急性呼吸窘迫综合征中线粒体依赖性细胞凋亡
DOI：
10.1038/s41374-019-0191-3
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发表时间：
2019-06-01
影响因子：
5
通讯作者：
Li, Yunfeng
中科院分区：
文献类型：
--
作者：
Li, Tao;Liu, Youtan;Li, Yunfeng
线粒体自噬去除功能障碍的线粒体，并且已知在几种疾病的发病机制中起重要作用;然而，线粒体自噬在急性呼吸窘迫综合征（ARDS）中的作用仍然知之甚少。虽然我们以前已经证明了虎杖苷（PD）改善脂多糖（LPS）诱导的ARDS，具体机制仍不清楚。在本研究中，我们的目的是确定PD是否激活帕金森病依赖的线粒体自噬，以防止LPS诱导的细胞凋亡和肺损伤。C57 BL/6小鼠体内气管内注射LPS（5 mg/kg），体外培养Beas-2B细胞，用0.5mM LPS诱导，建立ARDS模型。我们的研究结果表明，PD促进帕金易位到线粒体，并促进ARDS攻击的小鼠和LPS处理的Beas-2B细胞的线粒体自噬。然而，PD诱导的线粒体自噬在Parkin-/-小鼠和Parkin siRNA转染的细胞中被抑制，表明PD激活了Parkin依赖的线粒体自噬。此外，PD对LPS诱导的肺细胞凋亡和肺损伤的保护作用被抑制时，帕金耗尽在体内和体外。线粒体自噬抑制剂mitochondrial division inhibitor-1在体内抑制线粒体自噬和自噬相关基因7在体外沉默也阻断了PD介导的保护作用。我们的数据表明，帕金森病诱导的帕金森依赖性线粒体自噬提供了保护，对呼吸窘迫综合征依赖性细胞凋亡。
Mitophagy removes dysfunctional mitochondria and is known to play an important role in the pathogenesis of several diseases; however, the role of mitophagy in acute respiratory distress syndrome (ARDS) remains poorly understood. While we have previously demonstrated that polydatin (PD) improves lipopolysaccharide (LPS)-induced ARDS, the specific mechanism remains unclear. In present study, we aimed to determine whether PD activates Parkin-dependent mitophagy to protect against LPS-induced mitochondria-dependent apoptosis and lung injury. To establish the ARDS model, C57BL/6 mice were intratracheally injected with LPS (5 mg/kg) in vivo and Beas-2B cells were exposured to 0.5 mM LPS in vitro. Our results indicate that PD facilitates Parkin translocation to mitochondria and promotes mitophagy in ARDS-challenged mice and LPS-treated Beas-2B cells. However, PD-induced mitophagy was suppressed in Parkin-/- mice and Parkin siRNA transfected cells, indicating that PD activates Parkin-dependent mitophagy. Furthermore, the protective effects of PD against LPS-induced mitochondria-dependent apoptosis and lung injury were suppressed when Parkin was depleted both in vivo and in vitro. The inhibition of mitophagy with mitophagy inhibitor mitochondrial division inhibitor-1 in vivo and silencing of autophagy-related gene 7 in vitro also blocked the protective effects mediated by PD. Our data suggest that Parkin-dependent mitophagy induced by PD provides protection against mitochondria-dependent apoptosis in ARDS.